Tumor necrosis factor-α mediated pain hypersensitivity through Ret receptor in resiniferatoxin neuropathy

Neurogenic inflammation is an onset characteristic of small fiber neuropathy (SFN), which is attributed to neuropathic manifestations. Tumor necrosis factor-α (TNFα) is a cytokine that mainly mediates neurogenic inflammation through the ligand receptor TNF receptor 1 (TNFR1), and targeting TNFα/TNFR...

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Bibliographic Details
Published in:The Kaohsiung journal of medical sciences 2018-09, Vol.34 (9), p.494-502
Main Authors: Lu, Shui-Chin, Chang, Ying-Shuang, Kan, Hung-Wei, Hsieh, Yu-Lin
Format: Article
Language:English
Subjects:
Animals
Disease Models, Animal
Diterpenes - toxicity
Male
Mechanical allodynia
Mice
Pain Measurement
Proto-Oncogene Proteins c-ret - genetics
Proto-Oncogene Proteins c-ret - metabolism
Receptors, Tumor Necrosis Factor, Type I - metabolism
Resiniferatoxin
Ret receptor
Signal Transduction
Small Fiber Neuropathy - chemically induced
Small Fiber Neuropathy - metabolism
TNF receptor 1 (TNFR1)
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-α (TNFα)
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Summary:Neurogenic inflammation is an onset characteristic of small fiber neuropathy (SFN), which is attributed to neuropathic manifestations. Tumor necrosis factor-α (TNFα) is a cytokine that mainly mediates neurogenic inflammation through the ligand receptor TNF receptor 1 (TNFR1), and targeting TNFα/TNFR1 signaling is a direction toward treating inflammatory diseases and injury-induced neuropathy. However, the relationships between TNFα/TNFR1 signaling and Ret signaling, which mediates pain hypersensitivity, remains elusive. This study used resiniferatoxin (RTX), an ultrapotent analog of capsaicin, to generate a mouse model of SFN, leading to marked hindpaw edema (p = 0.013) and parallel the release of TNFα (p = 0.014), which was associated with the upregulation of Ret(+) neurons (p = 0.0043) and partial depletion of TNFR1 caused by colocalization with TRPV1 depleted by RTX. Pharmacological intervention of TNFα with etanercept (Enbrel®, Wyeth), a clinical application of TNFα blockers, relieved neurogenic inflammation and caused a reduction in hindpaw thickness (p = 0.03) and TNFα releases (p = 0.01), which were determined to be associated with the normalization of mechanical allodynia (p = 0.22). The extraction of either TNFR1(+) or Ret(+) neurons from total of TNFR1(+):Ret(+) neurons indicated that TNFR1(−)/Ret(+) neurons correlated with the mechanical threshold in an antiparallel fashion (r = −0.84, p 
ISSN:1607-551X
2410-8650
DOI:10.1016/j.kjms.2018.04.008